1. Field of the Invention
The present invention generally relates to fluid analysis methods and equipment.
More particularly, this invention relates to a fluid analysis device and method that utilize a micromachined filter to separate cells and/or particles from a fluid, such as a biological fluid, and means for sensing the material selectively separated from the fluid with the filter.
2. Description of the Related Art
Various fluids undergo some type of quantitative analysis to determine their composition and physical properties. Notable examples of such fluids include urine, blood, beverages, pharmaceutical mixtures, water, lubricating oils, fuels, and many industrial chemicals. With regard to urological analysis, a variety of parameters are typically measured during urology, including pH, specific gravity, and the amount of blood, leukocytes (white blood cells), glucose, protein, urobilinogen, bilirubin, ketones, nitrite, sodium, chlorine, potassium, magnesium, urea, uric acid, bicarbonate, sulfate, phosphate and calcium. The specific gravity of urine can be used as a screen to indicate renal and hepatic problems, with additional urinary tests being performed as necessary if a problem is indicated.
The specific gravity of urine has been measured by various methods, including ultrasonic and optical techniques as disclosed in U.S. Pat. Nos. 4,664,124 and 4,834,104, respectively. More recently, commonly-assigned U.S. patent application Ser. No. 09/468,628 to Tadigadapa et al. discloses a resonant mass flow and density sensor suitable for quantitative analysis of fluids. The sensor comprises a suspended tube that is vibrated at resonance. As fluid flows through the tube, the tube twists under the influence of the Coriolis effect. The degree to which the tube twists (deflects) when vibrated can be correlated to the mass flow rate of the fluid flowing through the tube, while the density of the fluid is proportional to the frequency of vibration. The tube is fabricated by micromachining, which as used herein denotes a technique for forming very small elements by bulk etching a substrate (e.g., a silicon wafer) or by surface thin-film etching, the latter of which generally involves depositing a thin film (e.g., polysilicon or metal) on a sacrificial layer (e.g., oxide layer) on a substrate surface and then selectively removing portions of the sacrificial layer to free the deposited thin film.
Various other parameters of interest in urological analysis have been measured using reagent test strips. However, there are drawbacks to the use of test strips, including the vulnerability to humidity, finger contamination, and erroneous results due to vitamin C intake prior to testing. Test strips also require a manual operation and the constant expense of replacement since they are consumed by the test.
Biological fluid filtration has also been utilized in the field of fluid analysis. For example, physical filtration of donated blood has been used for years to separate leukocytes from plasma. For urological applications, the concentration of leukocytes is often of interest, as their presence in urine can indicate a urinary tract infection from chronic catheter use as well as renal and hepatic problems. Leukocytes are larger (about twenty micrometers) than other blood or urine components, and so can be physically filtered. Micromachined filters, including silicon filters, capable of use in urological analysis have been proposed, as disclosed in U.S. Pat. Nos. 5,660,728 and 5,922,210.
While fluid analysis techniques and devices of the types described above have been successfully employed, there is a continuing effort to develop improved devices for performing fluid analysis. For example, the capability for continuous monitoring would be desirable, particularly in the form of remote monitoring of disabled catheterized patients. In addition, it would be desirable if components grouped into a single system could perform multiple analysis steps, such that an accurate diagnosis can be made with a single sample.
The present invention provides a method and device for performing fluid analysis utilizing a micromachined filter to separate cells and/or particles from a fluid, such as a biological fluid. The device has the additional capability of sensing the relative quantity of cells and/or particulate material selectively separated from the fluid with the filter. Multiple micromachined filters of this invention can be integrated into a single device that produces an electrical output for each of a number of urological parameters, providing a rapid and simplified interface capable of remote and continuous monitoring of a fluid.
According to a first aspect of the invention, the device is a micromachined filtering device comprising a substrate having a first surface, an oppositely-disposed second surface, and a thickness defined by and between the first and second surfaces. A plurality of vias extend through the thickness of the substrate, with the vias being spaced apart and having approximately equal diameters that prevent passage through the substrate of materials (e.g., cells and/or particles) having a diametrical dimension greater than the diameters of the vias, while permitting passage through the substrate of a fluid and any other materials present in the fluid and having a diametrical dimension less than the diameters of the vias. First and second electrodes are, located on the first surface of the substrate so that the materials too large to pass through the vias, and have therefore collected at the first surface of the substrate, will electrically connect the first and second electrodes to produce an output signal in proportion to the amount of the material collected.
As a result of the construction of the device, the present invention makes possible a method of quantitatively analyzing a fluid by flowing the fluid through the vias in the substrate, whereby the fluid and any cells and/or particles smaller than the vias are permitted to pass through the substrate, while cells and/or particles larger than the vias are prevented from passing through the substrate, such that the larger cells/particles collect at the first surface of the substrate. The amount of the collected cells/particles at the first surface of the substrate is indicated by the output signal obtained from the electrodes.
Fluid filtering in accordance with this invention may be preceded or followed by additional analysis, such as the measurement of specific density, pH, and various constituents detected with chemical sensors. In the case of urological analysis, such constituents include glucose, protein, urobilinogen, bilirubin, ketones, nitrite, pH, sodium, chlorine, potassium, magnesium, urea, uric acid, bicarbonate, sulfate, phosphate, and calcium. With the present invention, such analysis can be preformed on multiple substrates within a single device, yielding a single-system sensing and filtering system.
Other objects and advantages of this invention will be better appreciated from the, following detailed description.